About this item:

282 Views | 189 Downloads

Author Notes:

See publication for full list of authors.

Correspondence to: Richard H Duerr, MD, Room : BSTWR-S704, Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15213; duerr@pitt.edu; tel: (412) 648-9497; fax: (412) 383-8864.

See publication for full list of author contributions.

Disclosures: Nothing to disclose.

Subjects:

Research Funding:

The following support for this work is acknowledged by the authors whose initials or names are in parentheses following each source of support.

The NIDDK IBD Genetics Consortium is supported by National Institutes of Health (NIH) grants U01DK062413 (DPBM, J Braun), U01DK062420 (RHD, MDR), U01DK062422 (JHC, KYH, DDP), U01DK062429 (JHC, LPS, YS), U01DK062423 (MSS, RM, JMS), U01DK062431 (SRB), U01DK062432 (JDR).

This work was also supported by NIH grants F30DK098927 (KYH), P01DK046763 (SRT, J Braun, DPBM), P30CA016042 (J Braun), R01CA141743 (RHD), R01DK087694 (SK), R01DK092235 (JHC, KYH), R01DK098231 (SK), R01HS021747 (DPBM), T32DK007180 (JPJ), T32GM007205 (KYH), U01AI067068 (DPBM), U54DE023798 (J Braun), and UL1TR000124 (J Braun).

Additional sources of support included the Crohn’s and Colitis Foundation of America (J Braun, HH), Deutsche Forschungsgemeinschaft (DFG BR 1912/6-1) (SRB), Deutsche Forschungsgemeinschaft (DFG; projects Ni575/7-1 and Ni 575/4-1) (J-HN), Else Kröner-Fresenius-Stiftung (Else Kröner Exzellenzstipendium 2010; 2010_EKES.32) (SRB), Inflammatory Bowel Disease Genetic Research Chair at the University of Pittsburgh (RHD), Institutional Development Fund The Children’s Hospital of Philadelphia (HH), Örebro University Hospital Research Foundation (JH), Royal Brisbane and Women’s Hospital Research Foundation (GR-S), Sanford J Grossman Charitable Trust (JHC), SUCCESS (JHC), Swedish Research Council (521-2011-2764) (JH), Swedish Research Council (VR 2010–2976) (M D’Amato), Swedish Research Council (VR 2013–3862) (M D’Amato), Swiss National Science Foundation (SNF) 146290 (J-HN), The Eli and Edythe Broad Foundation, Proposal No. IBD-0164R (CB), The European Union (DPBM), The Kenneth Rainin Chair for IBD Research (J-PA), The Leona M and Harry B Helmsley Charitable Trust (DPBM), and The National Health and Medical Research Council (APP498405) (GR-S).

The authors thank the following investigators for providing additional control samples: M Ilyas Kamboh with support from NIH grants R01AG030653, R01AG041718, P50AG005133, R01AG007562, and R01AG023651; David C Whitcomb with support from NIH grant R01DK061451; Todd Lencz; and Peter K Gregersen.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Gastroenterology & Hepatology
  • Genetics
  • Inflammatory Bowel Diseases
  • Microbiota
  • INFLAMMATORY-BOWEL-DISEASE
  • ZINC TRANSPORTER
  • GENETIC-VARIANTS
  • SUSCEPTIBILITY LOCI
  • RISK
  • ZIP8
  • EXPRESSION
  • BACTERIA
  • CELLS
  • IBD

A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition

Show all authors Show less authors

Tools:

Journal Title:

Gastroenterology

Volume:

Volume 151, Number 4

Publisher:

, Pages 724-732

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Background & Aims Genome-wide association studies have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn's disease (CD) and ulcerative colitis remain incompletely defined. Here, we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip (San Diego, CA). Methods Genotyping was performed in 10,523 IBD cases and 5726 non-IBD controls. There were 91,713 functional single-nucleotide polymorphism loci in coding regions analyzed. A novel identified association was replicated further in 2 independent cohorts. We further examined the association of the identified single-nucleotide polymorphism with microbiota from 338 mucosal lavage samples in the Mucosal Luminal Interface cohort measured using 16S sequencing. Results We identified an association between CD and a missense variant encoding alanine or threonine at position 391 in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 alanine 391 threonine, rs13107325) and replicated the association with CD in 2 replication cohorts (combined meta-analysis P = 5.55 × 10 -13 ). This variant has been associated previously with distinct phenotypes including obesity, lipid levels, blood pressure, and schizophrenia. We subsequently determined that the CD risk allele was associated with altered colonic mucosal microbiome composition in both healthy controls (P =.009) and CD cases (P =.0009). Moreover, microbes depleted in healthy carriers strongly overlap with those reduced in CD patients (P = 9.24 × 10 -16 ) and overweight individuals (P = 6.73 × 10 -16 ). Conclusions Our results suggest that an SLC39A8-dependent shift in the gut microbiome could explain its pleiotropic effects on multiple complex diseases including CD.

Copyright information:

© 2016 by the AGA Institute

Export to EndNote